Counterregulatory Response to Hypoglycemia During a Hypoglycemic Clamp in People with Type 2 Diabetes Treated with Tirzepatide

Thomas R. Pieber^1*Eva Svehlikova²Shweta Urva³Axel Haupt³Chunmei Zhou³Tamer Coskun³Vera Höller²Gabriele Fluhr²Chrisanthi A. Karanikas³Zvonko Milicevic⁴Edward J. Pratt⁵

• ¹Department of Internal Medicine, Division of Endocrinology and Metabolism, Medical University of Graz, Graz, Austria
• ²Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
• ³Eli Lilly and Company, Indianapolis, United States
• ⁴Eli Lilly and Company, Vienna, Austria
• ⁵Lilly Centre for Clinical Pharmacology Pte Ltd, Biopolis, Singapore

Introduction: To evaluate counterregulatory hormonal responses during a hypoglycemic clamp with tirzepatide. Methods: Participants with type 2 diabetes (N=42) were randomized to tirzepatide (15 mg) or placebo for 12 weeks in a crossover design, with a wash-out period of 8-10 weeks. The primary objective was the change in glucagon response during clamp-induced hypoglycemia from plasma glucose (PG) 100 mg/dL to nadir PG (45 mg/dL). Secondary measures were changes in responses of other counterregulatory hormones during clamp-induced hypoglycemia. Time to recovery from the nadir to 72 mg/dL and hypoglycemic symptom scores using the 7-point Edinburgh Hypoglycemia Symptom scale were also assessed. Results: At 12 weeks, HbA1c change from baseline was -1.5% with tirzepatide versus +0.5% with placebo. During induced hypoglycemia, mean PG levels at nadir were 44.5 mg/dL with tirzepatide and 47.5 mg/dL with placebo. Increases in glucagon from PG 100 mg/dL to nadir PG and during recovery from the nadir to 72 mg/dL did not differ between treatments (p=0.756 and p=0.565, respectively). Growth hormone and adrenaline responses did not differ between treatments. Cortisol and noradrenaline responses were delayed with tirzepatide, consistent with lower hypoglycemic symptom scores at nadir observed during tirzepatide treatment periods versus placebo (p=0.007). The proportion of participants aware of hypoglycemia did not differ between treatments. Discussion: The response of the key counterregulatory hormone glucagon to induced hypoglycemia was maintained with tirzepatide.